Process for the preparation of diazomethane

ABSTRACT

A method for the production of diazomethane comprising the steps of a) feeding a base and a diazomethane precursor into a reactor vessel; b) generating gaseous diazomethane by allowing the base and the gaseous diazomethane precursor to react; and c) removing the gaseous diazomethane using a diluent gas.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of PCT Application No.PCT/GB00/03563 filed Dec. 15, 2000, and claims the benefit of UnitedKingdom Application No. GB 9930454.5 filed Dec. 23, 1999, the contentsof which are incorporated by reference in this disclosure in theirentirety.

BACKGROUND

Diazomethane (CH₂=N=N, also known as azimethylene or diazirine) is ahighly reactive gas with a wide range of utility in chemical syntheses.It reacts rapidly with carboxylic acids to form the corresponding methylesters, generally in high yield, with the evolution of gaseous nitrogen.In like manner diazomethane reacts with phenols, enols and alcohols toform methyl ethers with concomitant release of nitrogen; the rate ofreaction depending on the acidity of the substrate. A further example ofits use is the formation of carbon to carbon bonds with substrates suchas acid chlorides and anhydrides. The so formed diazoketones arethemselves useful intermediates. Further examples are its use incycloaddition reactions with olefins to form cylopropanes and nitrogenheterocycles. Similarly chain extension or ring expansion of ketones andconversion of ketones to epoxides can be readily achieved withdiazomethane. Still further examples of its use include formation ofviral protease inhibitors. A number of viral protease inhibitorsincluding those used to combat HIV are derived from three-carbon aminoacid isosteres. An example of these viral protease inhibitors isNelfinivir Mesylate (Agouron Laboratories). The crucial three-carbonfragment can be built from a two-carbon functionalized amino acid usingdiazomethane in a modified Arndt-Eistert reaction. This approach isparticularly attractive since reaction with diazomethane does notcompromise the chiral integrity of the amino acid.

Diazomethane is a powerful carcinogen, allergen and is highly poisonous.However the principle impediment to its use is that it is highlyexplosive. While the toxic properties of diazomethane can be obviated byjudicious plant design and good manufacturing practice, its sensitivityto explosion places greater restraints on its use. The technicalliterature for the lab-scale synthesis of diazomethane cautions againstthe use of ground-glass joints and specifically designed firepolishedglassware is recommended. The Aldrich Chemical Company, Inc., Milwaukee,Wis., USA markets a “large-scale” DIAZALD® apparatus capable ofgenerating a solution of up to 300 millimoles of diazomethane in diethylether by single batch reaction. See Black, T. H., “The Preparation andReactions of Diazomethane,” Aldrichimica Acta 16(1) 3-10 (1983).

A “large-scale” preparation is disclosed by Acevedo et al in U.S. Pat.No. 5,459,243, “Apparatus and Processes for the Large Scale Generationand Transfer of Diazomethane,” issued Oct. 17, 1995. The reactionsdisclosed are performed on the 100 millimole scale and generate dilutesolutions of diazomethane in dichloromethane.

A batch process for the production of gaseous diazomethane, “A NewMethod for the Preparation of Diazomethane” is disclosed by De Boer, T.H. J., and Backer, H. J. See Recueil 73 229-234 (1954). The processcomprises introducing a solution of potassium hydroxide in a mixture ofCarbitol—water to p-toly sulphonylmethylnitrosamide in anisole. A gentleflow of nitrogen is passed through the apparatus and the liberatedgaseous diazomethane is obtained in 48% yield. The paper goes on todisclose that when the diazomethane was absorbed immediately in anexcess of benzoic acid in ether, the yield was 63%.

More recently Chemistry in Industry, 21 Feb. 1994, page 122/123, in afollow up letter to a publication in the same journal dated 5 Nov.,1990, cautions against the production of gaseous diazomethane because ofthe explosive risks. This is consistent with Bernd Eistert—“Synthesiswith Diazomethane” which states “Gaseous diazomethane, even on dilutionwith nitrogen, likewise can undergo explosive decomposition, especiallyat temperatures of 100° C. or higher”.

Indeed it is because of the explosive nature of gaseous diazomethanethat the skilled man has tended towards production and use ofdiazomethane in dilute solutions.

Aerojet—General Corporation (“Aerojet”) is the only company to date tohave published procedures to produce diazomethane on a truly largescale.

A large-scale batch production process for the production of solutionsof diazomethane is disclosed by Aerojet in U.S. Pat. No. 5,817,778,“Large Scale Batch Process for Diazomethane,” issued Oct. 6, 1998 andEuropean Patent Publication No. EP 0 916 649 A1, “Large Scale BatchProcess for Diazomethane,” published can 19 1999. Preparations ofdiethyl ether solutions of diazomethane are disclosed on the 50gram-mole to 25,000 gram-mole scale.

A continuous process for the production of solutions of diazomethane hasbeen disclosed by Aerojet in U.S. Pat. No. 5,854,405, “ContinuousProcess for Diazomethane from an N-methyl-N-Nitrosamine and fromMethylurea through N-Methyl-N-Nitroso Urea,” issued Dec. 24, 1998 andEuropean Patent Publication No. EP 0 916 648 A1, “Continuous Process forDiazomethane,” published can 19 1999. This procedure involves dissolvingan N-methyl N-nitroso amine in a mixture of two organic solvents—one ofwhich is at least partially water miscible and dissolves theN-methyl-N-nitrosoamine, and the other is one that is substantially lesswater-miscible than the first and forms a separate phase with water anddissolves diazomethane. A stream of this solution is combined with astream of an aqueous inorganic base, the aqueous and organic phases arepermitted to settle after a suitable residence time and the phases areseparated, the diazomethane being recovered as an organic solution. Itis stated that because all the stages of the process can be conducted inthe liquid phase, the formation of diazomethane vapor is avoided and therisk of detonation is reduced or eliminated. However, the processisolates the diazomethane in a flammable organic solvent which providesa fire risk.

In view of the versatility of diazomethane and its associated hazards asafe and efficient large-scale continuous process providing good yieldsand preferably obviating the need for volatile and flammable solventswhile maintaining a low overall inventory of diazomethane is desirable.

FIGURES

These and other features, aspects and advantages of the presentinvention will become better understood with regard to the followingdescription, appended claims, and accompanying FIGURE where:

FIG. 1 is a schematic diagram of a process according to the presentinvention.

DESCRIPTION

While the invention will be described in connection with certainpreferred embodiments, it is not intended to limit the invention to theparticular embodiments. On the contrary, it is intended to cover allalternatives, modifications and equivalent processes as can be includedwithin the spirit of the invention as defined by the appended claims.

The applicant has experimentally determined that the lower explosivelimit (LEL) of diazomethane is 3.9%. (The LEL is a limit defined inair). By “diluting” the diazomethane in an inert gas such as nitrogenthe explosive limit is increased to an experimentally determined valueof, in the case of nitrogen, 14.7% allowing the applicant to operate athigher concentrations of diazomethane safely.

According to the present invention there is provided a continuous methodfor the production of diazomethane comprising the steps of feeding:

-   -   a diazomethane precursor, and    -   a base into a reactor vessel where they react to generate        diazomethane, and removing the resulting diazomethane as a gas.

In order to maintain a steady state operation the resultant waste steamis removed. The waste stream can comprise any unreacted reactants,by-products of the reaction, solvents and any residual diazomethaneremaining in solution.

Preferably the diazomethane precursor and the base are co-fed into thereactor vessel in a continuous stream and the diazomethane gas and theresultant waste stream are removed from the reactor vessel in acontinuous manner. Alternatively the diazomethane precursor and base canbe fed into the reactor vessel as intermittent or pulsed streams and thediazomethane gas and the waste stream can be removed from the reactorvessel as intermittent or pulsed streams.

Preferably the diazomethane precursor is dissolved in a first solventand the base is dissolved in a second solvent.

It is however possible for the base to be fed into the reactor vessel ina solid form and/or a liquid diazomethane precursor to be selectedthereby obviating the need for one or more of the first and secondsolvents.

In yet another embodiment the first solvent and second solvent are oneof the same solvent or a mixture of the first and second solvent.

Preferably the generation and removal of diazomethane gas isaided/effected by the use of a sparge diluent gas, which can beintroduced above (top-surface) and/or below (sub-surface) the reactionmixture. A sub-surface sparge diluent gas aids the mixing of thereaction mixture and helps displace the diazomethane gas from thereaction mixture. A top-surface diluent sparge further assists todisplace the diazomethane gas. Both the top-surface and bottom surfacesparges act as diluents and are adjusted to achieve the desiredoperating conditions.

Preferably the flow rates of the sparge diluent gas are such that theconcentration of diazomethane gas is maintained below the explosive forthe diazomethane in said sparge diluent gas.

When the sparge diluent gas is nitrogen the concentration ofdiazomethane in nitrogen is preferably maintained at below 14.7%.

Preferably the diazomethane generated—and displaced by the diluentsparge gas—is continuously reacted with the intended substrate at a ratewhich minimizes the inventory of diazomethane within the reactionsystem.

By controlling the temperature of the reaction and controlling the flowrates of one or more of:

-   -   the diazomethane precursor;    -   the base;    -   the sparge diluent gas; and    -   the waste stream    -   a steady-state operation can be achieved at a given set of        reaction conditions. By maintaining the relative concentration        of the reactants at a steady state, high yields and high purity        diazomethane can be obtained.

The optimum steady state conditions are primarily a function of the rateof addition of the reactants (and any respective solvents used tointroduce them into the reactor vessel), their respective concentrationsin the reactor vessel, the rate at which the diluent sparge gas is fedinto the reactor vessel, the reaction temperature and the rate at whichthe waste stream and diazomethane gas are removed.

By monitoring the concentration of the resulting diazomethane gas, theprocess can thus be controlled to achieve the desired operatingconditions, for example, by controlling one or more of the factorseffecting steady state, to optimize production and maintain safeoperability.

In most cases the ratio of the base to diazomethane precursor ismaintained at from, for example, 1.0 to 1.5:1 molar equivalents.

More preferably the ratio of base to diazomethane precursor ismaintained in excess at from about 1.1 to 1.4:1 molar equivalent, andmost preferably at about 1.2:1 molar equivalents.

Preferably the diazomethane precursor is an N-methyl N nitroso compoundor a precursor thereof.

The preferred N-methyl N nitroso compounds are selected from the groupconsisting of N-methyl-N-nitroso-p-toluenesulphonamide;N-methyl-N-nitroso urea; N-nitroso-methylaminoisobutyl methyl ketone;N,N′-dimethyl-N,N′dinitrosoterephthalamide;-[N′-methyl-N′nitroso(aminomethyl)]benzamide and1-methyl-3-nitro-1-nitrosoguanadine.

The preferred diazomethane precursor isN-methyl-N-nitroso-p-toluenesulphonamide.

The first solvent is preferably selected to:

-   -   i) be non volatile, i.e. have a low vapor pressure;    -   ii) have a high boiling point;    -   iii) be non-flammable; and    -   iv) be water soluble.

By non-volatile it is preferred that the vapor pressure is below 5 mm at25° C. and most preferably below 1 mm at 20° C.

By high boiling point it is preferred that the boiling point is above95° C., most preferably above 150° C.

By non-flammable it is preferred that the flash point is above 55° C. asdefined under the UK Chemicals (Hazard Information for Packaging &Supply) Regulations 1994.

The preferred first solvents are shown in the table below whichadditionally give their flashpoint, boiling point and vapor pressure.

TABLE FLASH BOILING POINT POINT VAPOR SOLVENT (° C.) (° C.) PRESSUREDi(ethylene glycol) ethyl ether 96 202 0.08 mm (20° C.)N,N′Dimethylformamide 58 153  3.9 mm (25° C.) N,N′Dimethylacetamide 70153   2 mm (25° C.) Hexamethylphosphoramide 105 231 0.07 mm (740 mm)(25° C.) Dimethyl suphoxide 96 189 0.42 mm (20° C.) Tetramethylenesulphone 165 285 0.01 mm (20° C.)

They can be used alone or as mixtures of one or more of these with orwithout a second solvent.

The most preferred first solvent is dimethyl suphoxide.

The base can be an inorganic or organic base.

The preferred bases are inorganic bases, such as, for example, sodium,potassium and barium hydroxide. Most preferred is potassium hydroxide.

Organic bases which are suitable include, for example, sodium andpotassium methoxide, sodium and potassium ethoxide, sodium isopropoxide,sodium cyclohexoxide and quaternary ammonium or quaternary phosphoniumhydroxides or alkoxides such as tetra-n-butylammonium hydroxide,cetylpyridinium hydroxide, benzyltrimethylammonium ethoxide,tetraethylphosphonium hydroxide, and n-butyltriethylphosphoniumphenoxide.

The second solvent is preferably a polar solvent, most preferably wateror a mixture of polar solvents either with or without a first solvent.

In some cases the first and second solvent are one of the same solventor a mixture of the first and second solvents.

The sparge diluent gas can be any suitable gas that displaces or effectsremoval of the resulting diazomethane from the reaction mixture.Examples include nitrogen, helium, argon, carbon dioxide and air. Inertgases are preferred, and the most preferred is nitrogen.

Preferably a reaction temperature is maintained at between 25° C. and70° C., most preferably at about 40° C.

Any residual diazomethane which remains in the reaction mixture and isnot removed as a gas, is destroyed by passing the waste stream, into aquench tank containing an acid medium. Preferably the waste stream is asingle phase aqueous waste stream.

The pH of the acid medium is preferably between pH 4 and 6, mostpreferably about pH 5.5. The preferred acid is acetic acid although anysuitable inorganic or organic acid could be used.

The steady state is controlled by reference to the yield and purity ofthe resulting diazomethane gas and its concentration in the diluent gas.

The invention, and more particularly the selection of preferred featuresovercome a number of problems or disadvantages associated with the knownlarge scale processes for producing diazomethane. Some of the problemsand/or disadvantages associated with such processes are set out below:

-   -   They generally employ flammable or highly flammable solvents;    -   They employ highly volatile solvents;    -   They require a relatively large inventory of diazomethane;

The processes generally require condensation of the diazomethane/solventvapor stream;

-   -   The processes are bi-phasic and require efficient mixing and        subsequent separation by distillation or phase separation; and    -   The processes generate solutions of diazomethane, which can        limit the flexibility of the downstream chemistry.    -   The batch process requires mechanical agitation with the        incumbent risk of hot spots, leaking stirrer glands and also        requires the use of a phase transfer catalyst to achieve        improved yields.

The benefits of the method of the invention and more particularly thepreferred features of the invention are set out below:

-   -   The diazomethane is generated quickly and continuously removed        and reacted in downstream chemistry. The process therefore        operates with a very low inventory of diazomethane, minimizing        the principal explosive hazard; and    -   the diazomethane so generated is substantially free of solvents,        moisture and other contaminants. No additional drying of the        diazomethane gas stream is necessary. The yield and purity of        the diazomethane generated is very high and being substantially        free of solvents and contaminants, allows flexible use in        downstream chemical reactions.

The preferred solvents used in the process are non-volatile, have lowvapor pressures, high boiling points, are non-flammable, and are watersoluble. Environmental concerns arising from the process are thereforeminimized.

The solvents used are chosen to ensure high solubility of thediazomethane precursor while minimizing the concentration ofdiazomethane in solution.

The reaction system is a homogenous/single-phase system. The generationof diazomethane is therefore extremely rapid without the need for anycatalysts and the yield of diazomethane is in excess of 90%.

The diazomethane is generated in a reactor vessel of basic design. Thereactor vessel is a dedicated unit which requires no mechanicalagitation and has no moving parts.

Reactants can be continually co-fed into the reactor vessel. Theaddition rates can be accurately controlled allowing a steady stateoperation at the desired diazomethane concentration to be quicklyachieved and maintained.

The diazomethane generated is continually “stripped” from the reactorusing a top-surface and/or a subsurface diluent gas sparge. Bycontrolling the rate of diluent sparge gas, the yield of diazomethanecan be optimized

By continually monitoring the generation, concentration and use ofdiazomethane on a real-time basis good steady-state process control canbe achieved.

The process is highly flexible and very applicable to scale-up. Wastestreams are continually rendered free of diazomethane by the applicationof aqueous acid. Treated waste is a homogenous single-phase and allcomponents are soluble.

The invention will now be described in more detail by way of exampleonly with reference to the FIGURE which is a schematic diagram of aprocess of the invention and the method outlined below.

Referring to the schematic diagram a feed tank was charged with a 15%(w/w) solution of potassium hydroxide. A second feed tank was chargedwith a 22.1% (w/w) solution of N-methyl-N-nitroso-p-toluenesulphonamidein dimethyl suphoxide. Both tanks were connected via pumps and/orpressure fed feed tanks to liquid mass flow meters. Full instrumentationcontrol is provided for feeds, level/pressure, temperature and on-lineanalysis. The internal reactor surfaces are preferably polished tominimize rough surface issues. The reaction system has been specificallydesigned to promote laminar flow. The potassium hydroxide solution flowrate was set at 1.00 Kg/hour corresponding to a molar flow of potassiumhydroxide of 2.67 mol/hour. The N-methyl-N-nitroso-p-toluenesulphonamidesolution flow rate was set at 2.15 Kg/hour corresponding to a molar flowof N-methyl-N-nitroso-p-toluenesulphonamide of 2.22 mol/hour. Nitrogenwas fed sub-surface and top surface through two mass flow controllers.The subsurface flow was set at a rate of 0.98 L/minute and thetop-surface flow was set at a rate of 6.7 L/minute. Commencement of thediazomethane reaction caused the temperature of the reaction mixture torise cooling was applied to maintain the reaction temperature at thedesired set point of 40° C. The diazomethane/nitrogen stream wascontinually monitored to ensure the concentration of diazomethane in thegas phase remained constant and below the explosive limit. Theflow-rates of top-surface and/or subsurface nitrogen, potassiumhydroxide/water and N-methyl-N-nitroso-p-toluenesulphonamide/dimethylsuphoxide are adjusted to maintain the concentration of diazomethane atabout 10%. Typically at least 96% of the diazomethane produced isremoved in the gas phase.

The diazomethane generated was removed in the diluent gas sparge andcontinuously reacted in subsequent downstream chemistry to minimize theinventory of diazomethane in the reaction system. The reactor wascontinually drained in order to achieve a constant reactant mixturelevel and maintain a steady state operation. The waste stream which cancontain residual levels of diazomethane was rapidly quenched into a tankcontaining 80% aqueous acetic acid. The pH of the tank was maintained atpH 5.5. Waste from the reactor, typically contains about 4% residualdiazomethane. This procedure allows 90 g to 93 g of diazomethane to beproduced per hour. The maximum inventory of diazomethane at any instanceis 0.11 g.

The above reaction system is capable of producing 652 Kg of diazomethaneper year at 80% utilization. By increasing the respective flow rates andadjusting the reactor volume, the system is capable of generatingdiazomethane at the rate of 5-10 kilos per hour (or 40 to 80 metrictonnes per year) while maintaining the inventory of diazomethane in thereaction system at under 100 g.

Although the present invention has been discussed in considerable detailwith reference to certain preferred embodiments, other embodiments arepossible. Therefore, the scope of the appended claims should not belimited to the description of preferred embodiments contained in thisdisclosure.

1. A method for the production of diazomethane comprising the steps of:a) feeding a diazomethane precursor dissolved in a first solvent and abase dissolved in a second solvent into a reactor vessel; b) generatinggaseous diazomethane by allowing the base and the diazomethane precursorto react; and c) removing the gaseous diazomethane as a gassubstantially free of solvent using a diluent gas.
 2. The method ofclaim 1, further comprising the step of removing a waste stream from thereactor vessel.
 3. The method of claim 1, where the waste stream isremoved from the reactor vessel in a continuous stream.
 4. The method ofclaim 1, where the feeding step comprises feeding either thediazomethane precursor, or the base, or both the diazomethane precursorand the base into the reactor vessel in a continuous stream; and. wherethe removing step comprises removing the gaseous diazomethane gas fromthe reactor vessel in a continuous stream.
 5. The method of claim 1,where the waste stream is removed from the reactor vessel in anintermittent or pulsed stream.
 6. The method of claim 1, where thediazomethane precursor is dissolved in a first solvent and the base isdissolved in a second solvent; and where the first solvent is the sameas the second solvent.
 7. The method of claim 1, where the diluent gascomprises a sparge diluent gas.
 8. The method of claim 7, where thesparge diluent gas is introduced below the reaction mixture.
 9. Themethod of claim 7, where the sparge diluent gas is introduce below thereaction mixture.
 10. The method of claim 7, where the sparge diluentgas is introduced both above the reaction mixture and below the reactionmixture.
 11. The method of claim 7, where the concentration of gaseousdiazomethane gas is maintained in the sparge diluent gas at below theexplosive limit for the gaseous diazomethane.
 12. The method of claim11, where the sparge diluent gas is nitrogen; and where theconcentration of the generated gaseous diazomethane in the nitrogen ismaintained at below about 14.7%.
 13. The method of claim 1, where theamount of gaseous diazomethane generated is maintained at a steady stateby controlling one or more than one rate selected from the groupconsisting of the rate of feeding the diazomethane precursor, the rateof feeding the base, and the rate of removal of the gaseousdiazomethane.
 14. The method of claim 1, where the reactor vessel ismaintained at a temperature; and where the amount of gaseousdiazomethane generated is maintained at a steady state by controllingthe temperature.
 15. The method of claim 1, where the amount of gaseousdiazomethane generated is maintained at a steady state by controllingthe rate of removal of the waste stream.
 16. The method of claim 1,where the base and the diazomethane precursor are maintained in thereactor vessel at a ratio of from about 1.0 to about 1.5:1 molarequivalents of base:diazomethane precursor.
 17. The method of claim 1,where the base and the diazomethane precursor are maintained in thereactor vessel at a ratio at about 1.2:1 molar equivalents ofbase:diazomethane precursor.
 18. The method of claim 4, where thegaseous diazomethane generated is substantially insoluble in the firstsolvent.
 19. The method of claim 5, where the gaseous diazomethanegenerated is substantially insoluble in the second solvent.
 20. Themethod of claim 4, where the first solvent comprises a substanceselected from the group consisting of dimethyl sulphoxide, di(ethyleneglycol) ethyl ether, N,N′-dimethylformamide N,N′-dimethyl acetamide,hexamethylphosphoramide, tetramethylenesulphone and combinations of thepreceding.
 21. The method of claim 4, where the first solvent comprisesa polar aprotic solvent.
 22. The method of claim 4, where the firstsolvent comprises dimethyl sulphoxide.
 23. The method of claim 1, wherethe base is an inorganic base.
 24. The method of claim 1, where the basecomprises a substance selected from the group consisting of sodiumhydroxide and barium hydroxide.
 25. The method of claim 1, where thebase comprises potassium hydroxide.
 26. The method of claim 1, where thebase comprises an organic base.
 27. The method of claim 1, where thebase comprises a substance selected from the group consisting ofpotassium methoxide, sodium methoxide, potassium ethoxide, sodiumethoxide, sodium isopropoxide, sodium cyclohexoxide, a quaternaryammonium hydroxide, a quaternary ammonium alkoxide, a quaternaryphosphonium hydroxide and a quaternary phosphonium alkoxides.
 28. Themethod of claim 1, where the base comprises a substance selected fromthe group consisting of benzyltrimethylanmmonium ethoxide,cetylpyridinium hydroxide, n-butyltri-ethylphosphonium phenoxide,tetraethylphosphonium hydroxide and tetra-n-butlyammonium hydroxide. 29.The method of claim 1, where the diazomethane precursor comprises aN-methyl N nitroso compound or comprises a precursor of a N-methyl Nnitroso compound.
 30. The method of claim 1, where the diazomethaneprecursor comprises one or more than one substance selected from thegroup consisting of N-methyl-N-nitroso urea,N-[N′-methyl-N′-nitroso(aminomethyl)]benzamide,N-nitroso-β-methylaminoisobutyl methyl ketone,N,N′-dimethyl-N,N′-dinitrosoterephthalamide; and1-methyl-3-nitro-1-nitrosoguanadine.
 31. A method as claimed in claim 1,where the diazomethane precursor comprisesN-methyl-N-nitroso-toluenesulphonamide.
 32. The method of claim 5, wherethe second solvent comprises a polar solvent.
 33. The method of claim 7,where the sparge diluent gas comprises one or more than one gas selectedfrom the group consisting of an inert gas, carbon dioxide and air. 34.The method of claim 7, where the sparge diluent gas comprises one ormore than one gas selected from the group consisting of argon, heliumand nitrogen.
 35. The method of claim 7, where the sparge diluent gas isnitrogen.
 36. The method of claim 14, where the temperature is betweenabout 25° C. and about 70° C.
 37. The method of claim 14, where thetemperature is about 40° C.
 38. The method of claim 1, furthercomprising the step of feeding the waste stream into a quench tankcontaining an acid medium; and where the acid medium is selected toreact with residual gaseous diazomethane in the waste stream, therebyproducing reaction products that do not include diazomethane.
 39. Themethod of claim 38, where the quenched tank is maintained at a pHbetween about 4 and about
 6. 40. The method of claim 38, where thequenched tank is maintained at a pH of about 5.5.
 41. The method ofclaim any of claim 38, where the acid medium comprises one or more thanone acid selected from the group consisting of an inorganic acid and anaqueous solution of an organic acid.
 42. The method of claim 38, wherethe acid medium comprises acetic acid.
 43. The method of claim 1, wherethe reactor vessel in the feeding step comprises a stainless steelreactor vessel comprising: a) a base having a full bore bursting diskconnected to a quench tank; b) a heat transfer surface connected to aheating means, a cooling means or both a heating means and a coolingmeans; c) a thermoprobe inside the reactor vessel; d) a waste outletvalve situated between the base of the reactor vessel and the quenchtank; e) addition ports in the reactor vessel configured to supplymake-up materials to the head space of the reactor; and f) a top-surfacediluent gas sparge port in the reactor vessel configured to supplydiluent gas below to the head space of the reactor; g) a bottom surfacediluent gas sparge port in the reactor vessel configured to supplydiluent gas below the liquid level of the reactor; and h) a gas outletport in the reactor vessel configured to recover gas from the head spaceof the reactor.
 44. The method of claim 1, further comprising the stepof using the gaseous diazomethane gas in a downstream reaction.
 45. Themethod of claim 1, further comprising the step of storing the gaseousdiazomethane.